The present invention is directed to processes for the preparation of a dialkyl trans-piperidine-2,5-dicarboxylate via a trans substituted piperidine derivative of the formula ##STR2## wherein R is (C.sub.1 -C.sub.3)alkyl. Said trans-piperidine derivatives are particularly useful as intermediates in the synthesis of certain neuroleptic, racemic or optically active perhydro-1H-pyrido[1,2-a]pyrazines having the relative stereochemical formula: ##STR3## wherein Z is H or Cl;
Y is O or S; PA1 n is 1, 2, 3 or 4; and PA1 L and X are taken separately, X is H or (C.sub.1 -C.sub.2)alkyl and L is R.sup.a (CH.sub.2).sub.m CO where m is 0, 1, 2 or 3 and R.sup.a is (C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, phenyl, naphthyl, furyl, benzofuranyl, thienyl, benzothienyl, pyrrolyl, indolyl, isoindolyl or one of said groups substituted on aromatic or heteroaromatic ring with fluoro, chloro, (C.sub.1 -C.sub.2)alkyl or (C.sub.1 -C.sub.2)alkoxy; or PA1 L and X are taken together and are: ##STR4## where Y.sup.1 is CH.sub.2, S, O or NH; Y.sup.2 and Y.sup.3 are taken separately and Y.sup.2 and Y.sup.3 are each independently hydrogen or methyl, or Y.sup.2 and Y.sup.3 are taken together and are (CH.sub.2).sub.q ; p is 1 or 2; q is 2, 3, 4 or 5; and r is 0 or 1; ##STR5## where s is 0 or 1; and - - - represents a bond or no bond; ##STR6## where X.sup.1 is CH or N; ##STR7## where R.sup.b, R.sup.c and R.sup.d are each independently H or CH.sub.3 and - - - represents a bond or no bond; ##STR8## where R.sup.e is phenyl or phenyl substituted with F, Cl, (C.sub.1 -C.sub.2)alkyl or (C.sub.1 -C.sub.2)alkoxy; ##STR9## or a pharmaceutically acceptable acid addition salt thereof. PA1 (c) separating said trans derivative of the formula (II) from the mixture. According to either of these processes, the preferred value of each of R and R.sup.1 is methyl; and the preferred aldehyde is salicylaldehyde.
The compounds of the formula (A), their preparation and their utility as antipsychotics are fully described herein and in concurrently filed U.S. patent application Ser. No. 07/661,791 by Bright et al., for "Perhydro-1H-pyrido[1,2-a]pyrazine Derivatives Having Neuroleptic Activity."
Dimethyl trans-piperidine-2,5-dicarboxylate has been previously prepared by Mastafanova et al., Chemistry of Heterocyclic Compounds-Translated from Russian, v. 21, pp. 305-309 (1985), via trans-piperidine-2,5-dicarboxylic acid which was in turn obtained as an equilibrium mixture with cis-piperidine-2,5-dicarboxylic acid by prolonged heating of the cis-isomer at 200.degree. C. in a high pressure bomb in the presence of excess aqueous sodium hydroxide.
Yamada et al., J. Org. Chem., v. 48, pp. 843-846 (1983), have described a method for the racemization of optically active alpha-amino acids in which the amino acid is heated in a carboxylic acid (e.g., formic, acetic, or propionic acid) in the presence of an aliphatic or aromatic aldehyde.